title: HCV NS5A replication complex inhibitors. Part 5: discovery of potent and pan-genotypic glycinamide cap derivatives.
abstract: The isoquinolinamide series of HCV NS5A inhibitors exemplified by compounds 2b and 2c provided the first dual genotype-1a/1b (GT-1a/1b) inhibitor class that demonstrated a significant improvement in potency toward GT-1a replicons compared to that of the initial program lead, stilbene 2a. Structure-activity relationship (SAR) studies that uncovered an alternate phenylglycine-based cap series that exhibit further improvements in virology profile, along with some insights into the pharmacophoric elements associated with the GT-1a potency, are described.
authors.affiliation: Department of Medicinal Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. makonen.belema@bms.com
authors.forename: Makonen
authors.initials: M
authors.lastname: Belema
authors.forename: Van N
authors.initials: VN
authors.lastname: Nguyen
authors.forename: Denis R
authors.initials: DR
authors.lastname: St Laurent
authors.forename: Omar D
authors.initials: OD
authors.lastname: Lopez
authors.forename: Yuping
authors.initials: Y
authors.lastname: Qiu
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Good
authors.forename: Peter T
authors.initials: PT
authors.lastname: Nower
authors.forename: Lourdes
authors.initials: L
authors.lastname: Valera
authors.forename: Donald R
authors.initials: DR
authors.lastname: O'Boyle
authors.forename: Jin-Hua
authors.initials: JH
authors.lastname: Sun
authors.forename: Mengping
authors.initials: M
authors.lastname: Liu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fridell
authors.forename: Julie A
authors.initials: JA
authors.lastname: Lemm
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.forename: Jay O
authors.initials: JO
authors.lastname: Knipe
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Snyder
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D005838:Genotype; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D006207:Half-Life; D016174:Hepacivirus / Q000201:enzymology* / Q000235:genetics / Q000502:physiology; D008862:Microsomes, Liver / Q000378:metabolism; D008968:Molecular Conformation; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D005998:Glycine; D017361:Viral Nonstructural Proteins; C018556:glycine amide; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase